Nucleosides are glycosylamines consisting of a nucleobase (often referred to as simply base) bound to a ribose or deoxyribose sugar via a beta-glycosidic linkage. In medicine several nucleoside analogues are used as antiviral or as anticancer agents. Number of nuclear modifications has been reported in the literature in which the sugar moiety is locked in a certain conformation. However, access to collections of the distinctive small molecules by modification of the sugar moiety in a nucleoside is an important feature in the realm of chemical genetics and for identifying new therapeutic candidates.
Diversity oriented synthesis (DOS) conceptualized by Schreiber has certainly provided an impetus to rapidly accessing the complex small-molecule libraries. However, flexibility in modulating the structural characteristics remains the cornerstone of a successful hit to lead exploration. A strategy that integrates the conceptual advantages of DOS and the manipulation of chemical functionality in a target oriented synthesis could be a valuable tool in new drug discovery programs.
Designing a new class of conformationally restricted nucleosides based on modification of the glycosyl moiety by spirocyclicannulation has now been recognized as an attractive strategy for delivering molecular diversity.
In this respect, cycloaddition reactions particularly [2+2+2] alkynecyclotrimerization reaction in presence of a transition metal catalyst on sugar templates have been studied and considered to be strategically useful for synthesizing library of small molecules. The unique characteristic property of [2+2+2]-alkynecyclotrimerization is its high synthetic efficiency (with the formation of several C—C and/or C-heteroatom bonds in a single step), complete atom-economy, and the availability of a wide range of catalysts that can tolerate a myriad of protecting/functional groups.
Utilizing [2+2+2]-alkyne cyclotrimerization for building modified sugar (spiro)-annulated tricyclic homochiral scaffold and further utilization of these scaffolds for the synthesis of tricyclic nucleosides remains an important therapeutic approach for developing small molecules that control genetic disorders or infections.
Cyclotrimerization reaction on sugar templates has been less explored and limited mainly to the synthesis of C-aryl glycosides. [McDonald, F. E.; Zhu, H. Y. H.; Holmquist, C. R. J. Am. Chem. Soc. 1995, 117, 6605-6606; Yamamoto, Y.; Saigoku, T.; Ohgai, T.; Nishiyamaa, H.; Itohb, K. Chem. Commun. 2004, 2702-2703; Yamamoto, Y.; Hashimoto, T.; Hattori, K.; Kikuchi, M.; Nishiyama, H. Org. Lett. 2006, 8, 3565-3568; Novak, P.; Pohl, R.; Kotora, M.; Hocek, M. Org. Lett. 2006, 8, 2051-2054]. An early example in this context is an expedient synthesis of spirocyclic C-arylglycoside whose frame work is closely related to that of papulacandins by McDonald and co-workers [McDonald, F. E.; Zhu, H. Y. H.; Holmquist, C. R. J. Am. Chem. Soc. 1995, 117, 6605-6606]. Yamamoto and co-workers [Yamamoto, Y.; Saigoku, T.; Ohgai, T.; Nishiyamaa, H.; Itohb, K. Chem. Commun. 2004, 2702-2703; Yamamoto, Y.; Hashimoto, T.; Hattori, K.; Kikuchi, M.; Nishiyama, H. Org. Lett. 2006, 8, 3565-3568] and Kotora and co-workers [Kotora, M.; Hocek, M. Org. Lett. 2006, 8, 2051-2054] have independently reported a [2+2+2]-alkynecyclotrimerization approach for the synthesis of C-aryl ribosides and C-aryldeoxyribosides, respectively. A [2+2+2]-alkynecyclotrimerization on a sugar derived building block for constructing enantiomeric tricyclicmolecular skeletons consisting of isochroman units is disclosed by Ramana, C. V.; Suryawanshi, S. B. Tetrahedron Lett. 2008, 49, pg 445448.
Article titled “Carbohydrate-Based Molecular Scaffolding” by Ingrid Velter et. al in Journal of Carbohydrate Chemistry, 25:97-138, 2006 having DOI: 10.1080/07328300600733020 discloses the use of modified carbohydrates, such as sugar amino acids (SAA), iminosugars and polycyclic derivatives, as scaffolds for the generation of bioactive compounds, and the use of carbohydrates as building blocks or ligands for the production of polymers for biomedical applications.
Article titled “A simple cobalt catalyst system for the efficient and regioselective cyclotrimerisation of alkynes” by Gerhard Hilt et. al in Chem. Commun., 2005, 1474-1475 having DOI: 10.1039/b417832g describes the intermolecular cyclotrimerisation of terminal and internal alkynes catalysed by simple cobalt complexes such as a CoBr2 (diimine) under mild reaction conditions when treated with zinc and zinc iodide with high regioselectivity in excellent yields.
Article titled “Selective synthesis of C-arylglycosides via CpRuCl-catalyzed partially intramolecular cyclotrimerizations of C-alkynylglycosides” by Y. Yamamoto, T. Saigoku, in Org. Biomol. Chem, 2005, 3, 1768-1775 having DOI:10.1039/b503258j describes synthesis of C-arylglycosides by means of the CpRuCl-catalyzed [2+2+2]-cycloaddition of α,ω-diynes with C-alkynylglycosides under mild reaction conditions. The functional group compatibility of the ruthenium catalysis towards a wide variety of functional groups allows synthesis of interesting C-arylglycosides including anthraquinone C-glycosides, bis(C-glycosyl) benzenes as well as C-arylglycoside amino acids.
Article titled “Chemo- and regioselective crossed alkyne cyclotrimerisation of 1,6-diynes with terminal monoalkynes mediated by Grubbs' catalyst or Wilkinson's catalyst” by Bernhard Witulski et. al in Chem. Commun., 2000, 1965-1966 having DOI: 10.1039/b005636g; discloses crossed alkyne cyclotrimerisations mediated by Grubbs' catalyst [RuCl2(NCHPh)(PCy3)2] which allows the efficient synthesis of 4,6-substituted indolines with high regioselectivity, and is complementary to alkyne cyclotrimerisations mediated by Wilkinson's catalyst [RhCl(PPh3)3] allowing the regioselective synthesis of the corresponding 4,5-substituted isomers.
Several approaches are documented for the modification of nucleosides.
Article titled “Preparation of Highly Substituted 6-Arylpurine Ribonucleosides by Ni-Catalyzed Cyclotrimerization. Scope of the Reaction” by Pavel Turek et. al in J. Org. Chem., 2006, 71, 8978-8981 having DOI: 10.1021/jo061485y describes transition metal complex catalyzed cocyclotrimerization of protected alkynyl purine ribonucleosides with various diynes to give series of 6-arylpurine nucleosides that were further deprotected to free nucleosides. Cyclotrimerizations were obtained with a catalytic system Ni(cod)2/2PPh3. CoBr(PPh3)3 is employed as a catalyst for cyclotrimerization of with dipropargyl ether. In addition, Ni catalysis is used for direct cyclotrimerization of unprotected alkynylpurineribonucleosides to the corresponding 6-arylpurinylribosides.
Article titled “Synthesis of C-Aryldeoxyribosides by [2+2+2]-Cyclotrimerization Catalyzed by Rh, Ni, Co, and Ru Complexes” by PetrNovák, et. al in Org. Lett., 2006, 8, 2051-2054 having DOI:10.1021/o1060454m describes a novel approach to the synthesis of functionalized C-nucleosides wherein cyclotrimerization of C-alkynyldeoxyriboside with a variety of substituted 1,6-heptadiynes is carried out to obtain the corresponding C-aryldeoxyribosides in presence of catalysts selected from various transition metal complexes (Rh, Ir, Co, Ru, and Ni) preferably, RhCl(PPh3)3.
Article titled “The isochroman- and 1,3-dihydroisobenzofuran-annulation on carbohydrate templates via [2+2+2]-cyclotrimerization and synthesis of some tricyclic nucleosides” Tetrahedron, 2010, 66, pg 6085. discloses the feasibility of cyclotrimerization of sugar derived diynes and shown that the resultant products can be transformed to the tricyclic and C(3′)-spirobenzoisofuran-annulated nucleosides following a sequence of chemical transformations. However, the spiro-annulated nucleosides reported contains a pentopyranose unit (6-membered sugar unit). Also, this strategy is not sufficiently effective as the number of compounds to be accessed is restricted by the limited number of nucleobases available which are introduced at the penultimate step of the synthesis. In addition, it may require additional steps if one intends to place sensitive functional groups on the isobenzofuran ring. This has prompted us to look for an alternative approach which can effectively address the library size and the ease of alteration of the functional groups on the isobenzofuran ring. This has led us into the exploration of the key C(3′)-spiroannulation as the final step by means of [2+2+2]-cyclotrimerization of completely free nucleoside-diynes with alkynes which is the main theme of the current patent application and also we address the selective synthesis of spiroannulated nucleosides having the furanoside ring also.
The prior art approaches, however, have in general been executed in a target oriented way (one scheme one nucleoside). This causes a serious limitation in the collection of spironucleosides as each modification needs to be attended separately from the beginning of the synthesis.